Lymphocyte Function and Molecular Mechanisms of Enhanced Immune Reconstitution Following Sex Steroid Ablation and Hemopoietic Stem Cell Transplantation (HSCT).

Age-related thymic atrophy plays a significant role in delayed immune reconstitution in older recipients after hemopoietic stem cell transplantations (HSCT). Sex steroid ablation has been shown to reverse thymic atrophy and previously we have shown that in syngeneic and allogeneic models of HSCT, sex steroid ablation enhances immune reconstitution. Donor-derived HSC numbers, as well as precursor T and B cells are increased in castrated mice following HSCT. These primary changes lead to an increase in both T and B cells in the periphery. The current study examined both the molecular mechanisms behind this enhanced reconstitution and the function of the lymphocytes produced. Bone marrow (BM) and thymic stromal cell (TSCs) populations were analysed using RT-PCR and were tested for the production of growth factors previously implicated in immune reconstitution. Functional studies including proliferation and cytotoxicity assays and intracellular cytokine production showed that on a per cell basis, there was no difference between the T cells from castrated and sham-castrated mice, following allogeneic HSCT. In vivo immune function was assessed using a delayed type hypersensitivity assay. Six weeks after HSCT the DTH response was enhanced in the castrated mice compared to sham-castrated controls. The combination of a) the increased number of donor-derived lymphocytes and b) intact T cell function, result in an overall increase in immune response (as determined by DTH) in castrated recipients of allogeneic HSCT. This enhanced function may be related to changes seen in growth factor production in the thymus and bone marrow.